PROJECT SUMMARY/ABSTRACT Mounting evidence support a role of heart fat in the pathogenesis of coronary heart disease (CHD). Relative to the pericardium, two distinct heart fat depots can be defined; epicardial adipose tissue (EAT), the fat within the pericardium, and paracardial adipose tissue (PAT), the fat outside the pericardium. We have recently shown in the Study of Women?s Health Across the Nation (SWAN) cohort study that postmenopausal women have significantly greater volumes of heart fat than premenopausal women, and that higher volumes of heart fat, particularly PAT, are significantly associated with lower levels and a steeper perimenopausal decline of endogenous estradiol (E2). These findings indicate that heart fat could be a readily-detectable, noninvasive novel CHD risk marker for postmenopausal women and suggest a role of estrogens in heart fat accumulation that could be limited to PAT depot. Similar to endogenous estrogen, exogenous estrogens, also known as menopause hormone therapy (HT), could have a significant impact on heart fat accumulation and on associations linking heart fat volumes with risk of atherosclerosis in women. Additionally, type of HT regimens (e.g. oral vs. transdermal) could have differential effects on heart fat accumulation in postmenopausal women. Limited cross-sectional data are available linking heart fat, menopause, and CHD risk. The Kronos Early Estrogen Prevention Study (KEEPS) provides a unique opportunity to examine the differential effects of HT regimens on heart fat accumulation and their associations with atherosclerosis development overtime. KEEPS was a multi-center, randomized, placebo-controlled clinical trial of the effects of two HT regimens (oral and transdermal), compared to placebo, on 4-year progression of subclinical atherosclerosis among 727 early postmenopausal women. Baseline and follow-up data on heart fat volumes and subclinical atherosclerotic measure coronary artery calcification (CAC), in addition to data on HT use, medical history, cardiometabolic, inflammatory and adipocytokine markers were collected as part of KEEPS and a completed ancillary study to KEEPS. These existing data will be used to conduct a secondary analysis to assess the following specific aims: Aim 1: to assess the effect of oral and transdermal HT vs. placebo on heart fat accumulations over time; Aim 2a: to examine the longitudinal relationships of baseline volumes of heart fat depots and their changes with changes in subclinical atherosclerosis; and Aim 2b: to explore the extent to which HT regimens modify the longitudinal associations of heart fat depots with subclinical atherosclerosis. The planned study entails investigation of novel mechanisms by which aging and menopause contribute to raise in CVD risk in women. This proposal will provide key information on the ongoing debate on the cardiovascular impact of HT in postmenopausal women, and could be used to inform clinical decision-making in selecting women who are appropriate candidates for HT and balancing its risks and benefits in early postmenopausal women.